Abstract
Mitochondrial Ca2+ is a key regulator of organelle physiology and the excessive increase in mitochondrial calcium is associated with the oxidative stress. In the present study, we investigated the molecular mechanisms linking mitochondrial calcium to inflammatory and coagulative responses in hepatocytes exposed to high glucose (HG) (33mM glucose). Treatment of HepG2 cells with HG for 24 h induced insulin resistance, as demonstrated by an impairment of insulin-stimulated Akt phosphorylation. HepG2 treatment with HG led to an increase in mitochondrial Ca2+ uptake, while cytosolic calcium remained unchanged. Inhibition of MCU by lentiviral-mediated shRNA prevented mitochondrial calcium uptake and downregulated the inflammatory (TNF-α, IL-6) and coagulative (PAI-1 and FGA) mRNA expression in HepG2 cells exposed to HG. The protection from HG-induced inflammation by MCU inhibition was accompanied by a decrease in the generation of reactive oxygen species (ROS). Importantly, MCU inhibition in HepG2 cells abrogated the phosphorylation of p38, JNK and IKKα/IKKβ in HG treated cells. Taken together, these data suggest that MCU inhibition may represent a promising therapy for prevention of deleterious effects of obesity and metabolic diseases.
Highlights
The evidence suggests that insulin resistance in skeletal muscle, adipose and liver tissues plays an important role in development and initiation of type 2 diabetes (T2D) [1]
Insulin-stimulated Akt phosphorylation reduced after 24 h treatment of HepG2 cells with 33mM glucose (HG) indicating the development of hepatic insulin resistance (Fig 1A)
Given the link between high glucose condition and increased mitochondrial calcium in HepG2 cells, we investigated whether there is an association between MCU and inflammatory cytokines and coagulation factors in hepatocytes
Summary
The evidence suggests that insulin resistance in skeletal muscle, adipose and liver tissues plays an important role in development and initiation of type 2 diabetes (T2D) [1]. There has been strong evidence that hyperglycemia, hyperinsulinemia, hyperlipidemia, and pro-inflammatory states contribute to development of insulin resistance [2]. The liver as a vital member of the vertebrates plays a central role in coordination of the entire metabolism. Some of the main functions of the liver include gluconeogenesis, glycogenolysis, glycogenesis, lipogenesis, cholesterol synthesis, synthesis of blood coagulation factors such as fibrinogen and plasminogen activator inhibitor-1 (PAI-1).
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